The purpose of the proposed research is to investigate the response of the opioid receptor-coupled cyclic nucleotide metabolism to acute and chronic exogenous opioid encounter in specific brain regions. Particular focus will be placed upon calcium-calmodulin regulation of adenylate cyclase activity and upon neurotransmitter receptor coupled systems interacting with opioid receptors. The specific aims are: 1. To characterize the mechanisms of opioid receptor-coupled regulation of calcium-stimulated and calcium-inhibited forms of adenylate cyclase in specific brain regions. 2. To determine the opioid receptor coupling to calicum-calmodulin interactions and the subsequent effect on the biogenic amine-sensitive adenylate cyclase that requires calmodulin for coupling. 3. To systematically follow the course of alterations in these systems during prolonged exposure to exogenous opioid agonists. 4. To characterize the alterations in neurotransmitter receptor sensitivity to ligand in specific brain regions with the development of dependence and the eversability of those alterations following withdrawal of exogenous opioids. The aims of this research are related to our long term goals of investigating biochemical loci in the brain that may mediate various aspects of adaptation and how they may participate in the adaptive phenomena involved in addictive states.